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from both human epidemiology studies and animal studies. In January 1988, the expert panel of the National Cholesterol Education Program on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults listed 10 atherosclerotic risk factors predictive of coronary arterial atherosclerotic events (6). Risk factor number four was "smoking >10 cigarettes a day". William Clifford Roberts, Editor in Chief of The American Journal of Cardiolocry, recently stated that "cigarette smoking is not an independent atherosclerotic risk factor" (7). Dr. Roberts and others have made this statement based upon the observation that "In populations where serum total cholesterol levels are <150 mg/dl atherosclerotic events are rare even when cigarette smoking is widespread" (7). Cigarette smoke has not been shown to be atherogenic in animals. Rogers et al. (8) published an elegant study on the atherogenic potential of cigarette smoke in baboons in 1988. Baboons are considered to be an excellent animal model for atherosclerosis because they develop atherosclerosis in the wild, show increased risk in males, and respond to dietary cholesterol in a manner similar to humans. The following abstract is excerpted from their paper: "In separate experiments, we fed 30 male and 25 female baboons a diet enriched in cholesterol and saturated fat for periods of 3.3 and 2.6 years. Using operant conditioning with water rewards, we trained the animals to puff on smoking machines in a human-like 7

manner. Half of the animals smoked more than 40 cigarettes per day, while the remaining animals (controls) puffed air. Initially, the diet produced twofold (males) and threefold (females) elevations from baseline levels in serum cholesterol concentrations, but over the course of the experiments, the serum cholesterol decreased to 1.5 (males) and 2.0 (females) times baseline levels in both cigarette smokers and controls. Blood carbon monoxide concentration, plasma thiocyanate concentration, and urine cotinine concentration were significantly greater in smokers than in controls. Responses to smoking in males induced lymphocytosis, elevated fasting blood glucose concentration, and decreased seminal vesicle weight. The extent of atherosclerosis was examined after 2.8 (males) and 1.6 (females) years of smoking. Among males, the extent of lesions in carotid arteries was significantly greater in smokers than in controls, but there were no significant differences in atherosclerosis in the the aorta or the brachial, iliac-femoral, or coronary arteries. Among females, there were no significant differences in atherosclerosis between smokers and controls in any artery. These experiments show little effect of 2 to 3 years of cigarette smoke inhalation and concurrent modest elevation of blood carboxyhemoglobin on experimental atherosclerosis in the presence of moderate hyperlipidemia". Rogers et al. (8) summarized the literature on the atherogenic potential of cigarette smoke in other animals in their 1988 paper: 8

"Similar efforts to reproduce the putative atherogenic effect of cigarette smoking in other animal models also have failed. Fisher et al. (1974) found no effects of passive exposure to cigarette smoke on atherosclerosis in either normocholesterolemic or hypercholesterolemic rabbits. Turner and Topping (1975) observed no changes in the plasma triglyceride concentrations of normolipidemic squirrel monkeys exposed to cigarette smoke, and Raymond et al. (1983) also did not observe changes in plasma cholesterol and lipoprotein concentrations of normocholestrolemic macaques exposed to cigarette smoke. Hojnacki et al. (1981) reported subtle changes in the lipoproteins of White Carneau pigeons fed an atherogenic diet and exposed to cigarette smoke. However, there were no reports of effects on lesions." Analysis of Statement 3 Dr. Aronow's work from this time period is currently considered by EPA to be of diminished value. The following paragraph describing EPA's position is excerpted from EPA's report entitled "Revised Evaluation of Health Effects Associated with Carbon Monoxide Exposure" published in August 1984 (9): "Since the CO standard was proposed by EPA in 1980, news media reports appearing in early 1983 indicated that the Food and Drug Administration (FDA) raised questions regarding the technical 9

adequacy of several studies conducted by Dr. Aronow on experimental drugs, leading to FDA rejection of use of the drug study data. While there was no specific evidence that similar problems might exist for the CO studies conducted by Dr. Aronow, EPA judged that an independent assessment of these studies was advisable prior to a final NAAQS decision on CO. An expert committee was impaneled by EPA and met with Dr. Aronow to discuss his studies and to examine limited available data and records from his CO studies. In its report, the committee (chaired by Dr. Stephen M. Horvath, Director of the Institute of Environmental Stress, University of California-Santa Barbara) concluded that EPA should not rely on Dr. Aronow's data due to concerns regarding problems associated with the studies which substantially limit the validity and usefulness of those study results (Horvath et al., 1983). Dr. Aronow submitted a detailed reply to EPA that disputed, but did not effectively refute, the major points raised by the committee report (Aronow, 1983)." Analysis of Statement 4 An examination of the 95% confidence intervals listed in Table 1 does not support the contention that the ten studies conducted to date show a statistically significant increase in coronary heart disease risk associated with exposure to ETS. Of the four studies conducted on males, three (Gillis et al., 1984; Lee et al., 1986; 10

Svendsen et al., 1987) have 95% confidence intervals that go below 1.0, i.e., no increased risk. The 95% confidence interval of the fourth study, Helsing et al. (1988), goes down to 1.1. _ Of the eight studies conducted on females, five (Hirayama, 1984; Gillis et al., 1984; Garland et al., 1985; Lee et al., 1986; Humble et al., 1990) have 95% confidence limits that either include or go below 1.0. The 95% confidence limits of the other three studies approach 1.0 with left limit values of 1.1 (Helsing et al., 1988), 1.2 (Martin et al., 1986), and 1.3 (He, 1990). In the one study conducted on both sexes, Hole et al. (1989) reported a 95% confidence interval with a left limit of 1.2. Therefore, all of these studies are either statistically insignificant at the 95% level or are marginally significant. Analysis of Statement 5 The contention that "ETS causes heart disease" is not supported by the results of the ten epidemiology studies so far conducted. In addition, the large number of risk factors for atherosclerosis (serum cholesterol, hypertension, age, gender, exercise, diabetes, ethnicity, stress, obesity, family history, etc.) and the great difficulty in determining exposure to ETS make the conduction of valid ETS-coronary heart disease epidemiology studies difficult if not impossible. An examination of the lifestyle differences between smokers and nonsmokers and between 11

the spouses of smokers and the spouses of nonsmokers illustrates the potential for confounded results. There are several significant dietary differences between smokers and nonsmokers. Smokers consume a diet significantly higher in 'saturated fat and lower in fruits and vegetables than nonsmokers (10-12). Many studies have associated this dietary pattern with an increased risk for atherosclerosis and coronary heart disease. In addition, M.F. Oliver (13) recently suggested that smokers have a reduced intake of the polyunsaturated fatty acid linoleic acid. Low levels of linoleic acid in fat tissue are associated with increased coronary risk at both the population and individual levels (14). Smokers also exercise significantly less than nonsmokers (15). Lack of physical activity is one of the four major cardiovascular risk factors (16). There are also significant dietary differences between the spouses of smokers and the spouses of nonsmokers. Sidney et al. (17) recently reported that the self-reported mean dietary intake of carotene is lower in nonsmokers exposed to ETS at home than in nonsmokers not exposed to ETS at home. Dietary carotene intake is a good marker for vegetable consumption. The exposed subgroup also had a slightly higher mean body mass index despite its considerably lower mean age. The dietary differences between the spouses of smokers and the spouses of nonsmokers is to be expected considering the concordance of husband-wife dietary practices (18). Familial aggregation in physical fitness has also been .observed. The following abstract is excerpted from Perusse et 12 0

al.'s (19) paper entitled "Familial Aggregation in Physical Fitness, Coronary Heart Disease Risk Factors, and Pulmonary Function Measurements": "In order to test for the presence of familial aggregation in physical fitness and coronary heart disease risk factors, body fat, submaximal power output, muscular strength, muscular endurance, blood pressure, pulmonary functions, and several blood biochemical variables were measured in 304 nuclear families living in the Quebec city area. Analysis of variance indicated a larger between- family than within-family variation for all the variables. When all members of nuclear families were considered, intraclass correlations ranged from 0.21 to 0.34 (P < 0.01). Interclass correlations computed for various pairs of relatives revealed significant parent-child and sibling correlations for all variables (0.14 < r< 0.55; P < 0.01). On the other hand, spousal correlations tended to be lower but significant (0.10 < r< 0.30; P< 0.05) for all variables except subcutaneous fat and hemoglobin concentration..." Myers et al. (20) recently reported results from the Framingham Study that suggest that there is a familial similarity in lipoprotein cholesterol levels. An unfavorable lipoprotein cholesterol level is the most important atherosclerotic risk factor (8). The following is excerpted from Myers et al.'s abstract (20): 13

"Serum lipid and lipoprotein levels have been associated with the expression of coronary heart disesse (CHD) but the effects of personal habits as well as inheritance may influence -these variables. Lipoprotein values were obtained for 500 spouse pairs participating in the Framingham Study between 1968 and 1972 and 1,111 of their offspring (560 sons, 551 daughters) evaluated between 1971 and 1983. Age and sex adjusted values produced significant mid-parent to mid-offspring correlations of HDL (r = .34), LDL (r = .31), VLDL (r = .17) and total cholesterol (r = .34) (all p <.0001). When further adjusted for smoking and body mass index, correlations were consistently stronger: HDL (r = .39), LDL (r = .38), VLDL (r = .23) and total cholesterol (r = .34) (all p <.0001). Spouse pair correlations adjusted for age, sex, smoking and body mass index were significant for HDL (r = .18 p< .0001) but not for LDL (r = .04) or VLDL (r =.04)..... " REFERENCES 1. M.T. Kampman and G. Hornstra. No acute effect of cigarette smoking on bleeding time of habitual smokers. Thrombosis Research 51; 287-294, 1988. 2. R.R. Taylor et al. Whole blood platelet aggregation is not affected by cigarette smoking but is sex-related. Clinical and__Experimental Pharmacoloay & Physiology 14; 665-671, 1987. 3. Matti Hillbom et al. Platelet thromboxane formation and bleeding time is influenced by ethanol withdrawal but not by cigarette smoking. Thrombosis and Haemostasis 53(3); 419- 422, 1985. 4. T.W. Mead et al. Epidemiological characteristics of platelet aggregability. British Medical Journal 290; 1985. 14

5. R.F. Davis and J.W. Davis. The effect of smoking on the stressed template bleeding time. Annals of Clinical Research 15; 131-133, 1983. 6. The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med 1988; 148: 36-69. 7. William C. Roberts. Atherosclerotic risk factors- are there ten or is there only one? The American Journal of Cardioloav Volume 64 (8): 552-554, 1989. 8. W.R. Rogers et al. Cigarette smoking, dietary hyperlipidemia, and experimental atherosclerosis in the baboon. Experimental and Molecular Patholoay 48, 135-151 (1988). 9. US EPA. Revised evaluation of health effects associated wtih carbon monoxide exposure. August 1984. 10. Whichelow MJ, Golding JF, Treasure FP. Comparison of some dietary habits of smokers and non-smokers. British J of Addiction 1988; 83: 295-304. 11. Shibata A et al. Serum concentration of beta-carotene and intake frequency of green-yellow vegetables among healthy inhabitants of Japan. Int J Cancer 1989; 44: 48-52. 12. Hirayama T. Dietary habits in smokers. Statistical Methods in Cance_r Research, edited by William J. Blot, Takeshi Hirayama, and David G. Hoel, 1984, p. 93-94. 13. M.F. Oliver. Cigarette smoking, polyunsaturated fats, linoleic acid, and coronary heart disease. The Lancet, June 3, 1989, 1241-1243. 14. Nutrition Research Newsletter. Cigarette smoking affects linoleic acid intake. July 1989, p. 79. 15. Lazarus NB et al. Smoking and body mass in the natural history of physical activity: prospective evidence from the Alameda County Study, 1965-1974. Am J Prey Med 1989; 5(3): 127-135. 16. James O. Mason, Director, Centers for Disease Control. Opening statement to Senate committee. March 4, 1987. 17. Sidney S, Caan BJ, Friedman GD. Dietary intake of carotene in nonsmokers with and without passive smoking at home. Am J Epidemiol 1989; 129: 1305-1309. tn 0 15 -4 cn tD N OJ tfl .p

18. Kristian Lindsted and Jan W. Kuzma. Husband-wife diet concordance and changes in dietary practices by surviving spouses of cancer cases. Nutrition and Cancer Vol. 13, No. 3, 1990, p. 175-187. 19. Perusse L et al. Familial aggregation in physical fitness, coronary heart disease risk factors, and pulmonary function measurements. Preventive Medicine 1987; 16: 607-615. 20. Myer RH et al. Familial similarity in lipoprotein cholesterols: the Framingham Study. Am J Human Genetics 45(4, Supplement): A246, October 1989. 16